Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate

Assays that can determine the response of tumor cells to cancer therapeutics could greatly aid the selection of drug regimens for individual patients. However, the utility of current functional assays is limited, and predictive genetic biomarkers are available for only a small fraction of cancer therapies. We found that the single-cell mass accumulation rate (MAR), profiled over many hours with a suspended microchannel resonator, accurately defined the drug sensitivity or resistance of glioblastoma and B-cell acute lymphocytic leukemia cells. MAR revealed heterogeneity in drug sensitivity not only between different tumors, but also within individual tumors and tumor-derived cell lines. MAR measurement predicted drug response using samples as small as 25 μl of peripheral blood while maintaining cell viability and compatibility with downstream characterization. MAR measurement is a promising approach for directly assaying single-cell therapeutic responses and for identifying cellular subpopulations with phenotypic resistance in heterogeneous tumors.United States. National Institutes of Health (R01 CA170592)United States. National Institutes of Health (R33 CA191143)National Cancer Institute (U.S.) (U54 CA143874)United States. National Institutes of Health (NIH/NIGMS T32 GM008334

Measuring mass changes in single suspended and adherent cells, with applications to personalized medicine in Glioblastoma Multiforme (GBM)

Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biological Engineering, 2017.Cataloged from PDF version of thesis.Includes bibliographical references (pages 117-119).The increased precision offered by developments in suspended microchannel resonator (SMR) technology opens the possibility for measuring small mass changes in cells. Mass accumulation rate (MAR) measurements in single suspended cells over short periods of time have the potential for characterizing heterogeneous collections of tumorigenic cells and serve as a functional marker for the effects of anti-cancer drugs. In this thesis we adapt mass accumulation measurements for use in Glioblastoma Multiforme (GBM) patient-derived cell lines, exploring the heterogeneity between and within patient tumors, and validating the measurement as a predictor of drug susceptibility with response times on the order of 24 to 48 hours using an experimental MDM2 inhibitor. While MAR measurements can be performed on suspended single cells with high precision, it has not yet been adapted for measuring the growth of adherent cells. We develop a technique to measure mass accumulation in cells adhered to the inner surface of the resonator channel. To overcome challenges inherent in such a measurement, we use infrared imaging and multiple resonant modes to reveal the cell's position in the SMR, and utilize differential measurements from a second cantilever to account for frequency drift.by Nigel Shijie Chou.Ph. D